Ancient Viral DNA: Unlocking the Secret to Stronger Bones and More

KAUST research Ancient viral DNA

KAUST researchers have uncovered that LINE-1 RNA, a transposable element within the human genome, is pivotal in bone regeneration.

This discovery, which challenges the long-standing belief that such elements are mere ‘junk DNA,’ opens up innovative pathways for addressing osteoporosis and related conditions.

Nearly half of the human genome is composed of DNA remnants from ancient viral infections. These remnants, termed “transposable elements” (TEs), are increasingly recognized for their roles in regulating gene expression and contributing to disease progression.

Recently, a global research team led by KAUST scientists identified that a particular transposable element, LINE-1 RNA, has a beneficial role in enhancing bone repair, suggesting its potential in treating osteoporosis and similar ailments.

“Previously dismissed as ‘junk DNA,’ TEs were once thought to be either irrelevant or harmful,” explains Arianna Mangiavacchi, a research scientist at KAUST who collaborated with faculty member Valerio Orlando and other researchers on the study.

“However, we’re now discovering numerous positive functions for TEs, and our findings on bone repair contribute significantly to this growing field of knowledge.”

Research Findings and Experiments

The research conducted by Mangiavacchi and Orlando centers on aging and the body’s response to environmental stress over time. It is known that TE levels increase with age, yet their role in tissue health remains largely unexplored.

Earlier work by Mangiavacchi and her team hinted at a connection between LINE-1 RNA activity and bone health, prompting further investigation into the underlying mechanisms.

Initially, the team performed sequencing experiments on mice with bone fractures, discovering that TEs, particularly LINE-1 RNA, were upregulated for a brief period following the injury.

“Subsequent analysis revealed that LINE-1 RNA initiated a finely-tuned inflammatory response, which in turn activated a specific signaling pathway essential for fracture repair,” Mangiavacchi notes.

Implications for Osteoporosis

The team then explored the role of TEs in bone cells (osteoblasts) sourced from postmenopausal women with osteoporosis, as well as from a healthy control group.

They found that TEs, especially LINEs, were significantly upregulated in healthy femurs with high bone density, whereas those with low bone density and osteoporosis exhibited reduced LINE expression.

“We introduced synthetic LINE-1 RNA into these cell cultures, and the outcomes were strikingly evident,” Mangiavacchi shares.

“Osteoblasts treated with LINE-1 RNA exhibited a distinct phenotype, characterized by rapid and abundant bone matrix formation. Remarkably, cells derived from osteoporotic patients responded positively to the LINE-1 RNA treatment.”

“It appears that the human genome has co-opted viral TEs to initiate an inflammatory response to injury, thereby activating the innate immune system to repair bones and tissues.

This so-called ‘dark side’ of TEs has been deliberately integrated into our genome, enabling adaptation and resilience,” Orlando adds.

This groundbreaking discovery is protected by two patents, one licensed to the biotech company Altos Labs in California, and another to the start-up RepeatEra, co-founded by Orlando and Mangiavacchi, which aims to bring their pro-regenerative therapy to clinical trials.

“We suspect that this mechanism is not limited to bone repair, and that synthetic LINE-1 RNA therapies could have broader applications, from corneal regeneration to skin-protective treatments,” Mangiavacchi concludes. “We are eager to further explore these findings and uncover how TEs affect other cell types.”

Reference

“LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response” by Arianna Mangiavacchi, Gabriele Morelli, Sjur Reppe, Alfonso Saera-Vila, Peng Liu, Benjamin Eggerschwiler, Huoming Zhang, Dalila Bensaddek, Elisa A Casanova, Carolina Medina Gomez, Vid Prijatelj, Francesco Della Valle, Nazerke Atinbayeva, Juan Carlos Izpisua Belmonte, Fernando Rivadeneira, Paolo Cinelli, Kaare Morten Gautvik and Valerio Orlando, 1 July 2024, The EMBO Journal.

KAUST research Ancient viral DNA